An estimated 23 million Americans, or about 15% of the adult population, have high blood pressure. Of these, approximately one-half are unaware of their condition; of the one-half that are cognizant of their condition, only one-half are receiving drug therapy; and, of those on therapy, only one-half can be considered to be under control. High blood pressure, or hypertension, is the primary cause of more than 60,000 deaths each year and is an underlying cause in more than 1,500,000 heart attacks and strokes occurring each year in the United States. Nearly one-half of these heart attacks and strokes are fatal, while the majority of those victims who do not succumb are restricted in their activity.
Evidence suggests that the sympathetic nervous system plays an important role in ordinary or essential hypertension. Pharmacological agents that block or abolish the sympathetic input to the circulatory system act to lower blood pressure as well as plasma norepinephrine levels. Norepinephrine is a sympathomimetic hormone that acts as a neurotransmitters when released from sympathetic nerve endings in response to nerve impulses. When released, norepinephrine constricts the blood vessels resulting in a rise in blood pressure. The .alpha.-receptor blocking drug, N-(2-chloroethyl)-N-(1-methyl-2-phenoxyethyl)benzene-methanamine, hereinafter referred to by its generic name, phenoxybenzamine, has been reported to benefit some patients with hypertension. However, its low effectiveness and concomitant side-effects, such as postural hypotension, palpitations and problems with sexual function, have discouraged its use.
The compound N-(2,6-dichlorophenyl)-4,5-dihydro-1H-imidazol-2-amine, hereinafter referred to by its generic name, clonidine, is a potent antihypertensive agent. Considerable evidence suggests that clonidine acts at the .alpha.-adrenergic receptor sites in the brain to reduce blood pressure. In contrast to phenoxybenzamine, clonidine acts to mimic rather than to block the neurotransmitter norepinephrine at the .alpha.-adrenergic receptors. Clonidine acts both at the .alpha.-adrenergic receptors in the blood vessels to raise blood pressure as well as upon .alpha.-adrenergic receptors on certain neurons in the brain to lower blood pressure. At clinical doses, the latter mode of action usually predominates, resulting in a decrease in sympathetic activity, cardiac output and blood pressure.
Some of the side-effects of clonidine treatment, however, mitigate against its widespread usage, particularly with respect to its use in long-term maintenance therapy of essential hypertension. Thus, drowsiness, sleepiness, lethargy, dry-mouth, constipation, headache and fatigue have all been reported with clonidine treatment. Furthermore, in some patients treated for essential hypertension, the continued administration of high doses of clonidine results in the development of a tolerance with a resulting diminished, antihypertensive effectiveness of the drug, see Wing et al., Br. Med. J. 1, 136-8 (1977). Even more seriously, a sudden interruption or withdrawal of clonidine therapy will, in some instances, precipitate a rebound hypertension or hypertensive crisis, a potential hazard where patient compliance is lacking, see Hansson et al., Am. Heart J. 85, 605-10 (1973).
I have discovered that the conjoint administration of certain combinations of phenoxybenzamine and clonidine actually enhances the antihypertensive effect obtained with clonidine alone, thereby permitting the overall administration of decreased amounts of clonidine to the patient. The administration of decreased amounts of clonidine minimizes some or all of the undesirable effects of the drug, delays the problem of drug tolerance, and reduces the problem of rebound hypertension upon discontinuance of the drug, thereby providing hypertensive patients with increased benefits from this useful drug, not heretofore available.